Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity.
Angiogenesis depends on both cell adhesion and proteolytic mechanisms. In fact, matrix metalloproteinase 2 (MMP-2) and integrin alphavbeta3 are functionally associated on the surface of angiogenic blood vessels. A fragment of MMP-2, which comprises the C-terminal hemopexin-like domain, termed PEX, prevents this enzyme binding to alphavbeta3 and blocks cell surface collagenolytic activity. PEX blocks MMP-2 activity on the chick chorioallantoic membrane where it disrupts angiogenesis and tumor growth. Importantly, a naturally occurring form of PEX can be detected in vivo in conjunction with alphavbeta3 expression in tumors and during developmental retinal neovascularization. Levels of PEX in these vascularized tissues suggest that it interacts with endothelial cell alphavbeta3 where it serves as a natural inhibitor of MMP-2 activity, thereby regulating the invasive behavior of new blood vessels.
Brooks
P C
PC
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Silletti
S
S
von Schalscha
T L
TL
Friedlander
M
M
Cheresh
D A
DA
D000482:Allantois / Q000201:enzymology; D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D002823:Chorion / Q000201:enzymology; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology; D018093:Gelatinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006466:Hemopexin; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008545:Melanoma / Q000098:blood supply / Q000473:pathology; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D012160:Retina / Q000201:enzymology; D012171:Retinal Vessels / Q000201:enzymology; D014407:Tumor Cells, Cultured
D010446:Peptide Fragments; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins; D003094:Collagen; D006466:Hemopexin; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2